C-MYC-INDUCED APOPTOSIS IN POLYCYSTIC KIDNEY-DISEASE IS BCL-2 AND P53INDEPENDENT

The SBM mouse is a unique transgenic model of polycystic kidney diseas e (PKD) induced by the dysregulated expression of c-myc in renal tissu e. In situ hybridization analysis demonstrated intense signal for the c-myc transgene overlying tubular cystic epithelium in SBM mice. Renal proliferation index in SBM kidneys was 10-fold increased over nontran sgenic controls correlating with the presence of epithelial hyperplasi a. The specificity of c-myc for the proliferative potential of epithel ial cells was demonstrated by substitution of c-myc with the proto-onc ogene c-fos or the transforming growth factor (TGF)-alpha within the s ame construct. No renal abnormalities were detected in 13 transgenic l ines established, indicating that the PKD phenotype is dependent on fu nctions specific to c-myc. We also investigated another well character ized function of c-myc, the regulation of apoptosis through pathways i nvolving p53 and members of the bcl-2 family, which induce and inhibit apoptosis, respectively. The SBM kidney tissues, which overexpress c- myc, displayed a markedly elevated (10-100-fold) apoptotic index. Howe ver, no significant difference in bcl-2, bar, or p53 expression was ob served in SBM kidney compared with controls. Direct proof that the hei ghtened renal cellular apoptosis in PKD is not occurring through p53 w as obtained by successive matings between SBM and p53(-/-) mice. All S BM offspring, irrespective of their p53 genotype, developed PKD with i ncreased renal epithelial apoptotic index. In addition, overexpression of both bcl-2 and c-myc in double transgenic mice (SBB+/SBM+) also pr oduced a similar PKD phenotype with a high apoptotic rate, showing tha t c-myc can bypass bcl-2 in vivo. Thus, the in vivo c-myc apoptotic pa thway in SBM mice occurs through a p53- and bcl-2-independent mechanis m. We conclude that the pathogenesis of PKD is c-myc specific and invo lves a critical imbalance between the opposing processes of cell proli feration and apoptosis.